: Disturbances in free fatty (FFA) metabolism are a characteristic feature of type 2 diabetes mellitus and type 2 diabetic individuals demonstrate daylong increased plasma FFA levels. Interestingly, disturbances in FFA metabolism are observed in normal glucose tolerant, insulin-resistant, genetically predisposed individuals long before the onset of overt diabetes, and in these offspring, as well as in type 2 diabetic subjects, adipose tissue is resistant to the antilipolytic effects of insulin. This raises the interesting possibility that FFA act as metabolic messenger which, when released in increased amounts, can impair insulin action in muscle and liver, i.e., "lipotoxicity." In the present grant we shall use the euglycemic insulin clamp in combination with indirect calorimetry, radioisotope techniques, and vastus lateralis muscle biopsy, (with measurement of key insulin signaling events) to compare and contrast the effects of various FFA lowering agents and inhibitors of FFA oxidation on basal and insulin-mediated muscle and hepatic glucose metabolism, as well as on fat topography in type 2 subjects.